Regulation of cell growth by S6 kinase signaling pathway

Abstract

The regulation of cell growth has been intensively studied for a decade and PI3K/Akt/mTOR/p70S6k cascade has been assigned to a major signaling pathway modulating the cell growth. Much work has focused on unveiling the signaling components of the pathway and has revealed many regulators including AMP kinase, Tuberous sclerosis complex 1/2 (TSC1/2), and Rheb GTPase. In many cells, an increase in levels of intracellular cyclic AMP (cAMP) diminishes cell growth and promotes differentiation, and in certain conditions cAMP is even antagonistic to the effect of growth factors. Here, I showed that cAMP has inhibitory effects on the phosphatidylinositol 3-kinase (PI3K)/PDK1/Akt/p70S6k signaling pathway. cAMP potently inhibits the activities of p70S6k and Akt by inhibiting PDK1 translocation to the plasma membrane. Finally, cAMP was found to inhibit the lipid kinase activity of PI3K and to decrease the levels of phosphatidylinositol 3, 4, 5-triphosphate ($PIP_3$) in vivo, which are required for the membrane localization of PDK1. Collectively, these data strongly support that the cAMP-dependent signaling pathway inhibits p70S6k and Akt activity by blocking the coupling between Akt and its upstream regulators, PDK1, in the plasma membrane. Next, to further investigate the regulators of p70S6k, I identified UNC-51-like kinase (ULK), a novel signaling component regulating p70S6k through Drosophila genetic screening. The reduction of dULK gene dosage enhanced cell growth caused by overexpression of dS6k and partially restored the decreased cell size, the lethality, and developmental delay in dTor-deficient mutant fly. The lethality of dULK-deficient fly was also rescued by the reduction of dS6k or dPDK1 expression. In addition, the phosphorylation and activation of p70S6k were potently inhibited by ULK in a ULK activity-dependent manner in HEK293T cells. Furthermore, my data indicated that ULK could phosphorylate Ser 389 residue of PDK1 linker region and modulate the functio...